Activation of Notch3 in osteoblasts/osteocytes causes compartment-specific changes in bone remodeling

Canalis, Ernesto; Zanotti, Stefano; Schilling, Lauren; Eller, Tabitha; Yu, Jungeun

doi:10.1016/j.jbc.2021.100583

Cited by 5 publications

(12 citation statements)

References 81 publications

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“…Previous studies have shown that LPS (Dong et al, 2018b), IL-6,TGF-b, parathyroid hormone -related protein (PTHrP) (Yasuda, 2021), IGF-1 (Huang et al, 2018;Yasuda, 2021), and other inflammatory factors facilitate RANKL expression. During osteoclast differentiation, activated T nuclear factor (NFATc1) is a major transcription factor, which can be activated by RANKL binding to its receptor RANK to promote osteoclast differentiation (Canalis et al, 2021). Additionally, TNF receptorassociated factor 6 (TRAF6) in osteoclast precursors is necessary to mediate RANKL-induced NF-kB activation and osteoclast formation and activation.…”

Section: Ranklmentioning

confidence: 99%

Mechanisms of bone remodeling and therapeutic strategies in chronic apical periodontitis

Xu-tao

Wan

Liu

et al. 2022

Front. Cell. Infect. Microbiol.

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Chronic periapical periodontitis (CAP) is a typical oral disease in which periodontal inflammation caused by an odontogenic infection eventually leads to bone loss. Uncontrolled infections often lead to extensive bone loss around the root tip, which ultimately leads to tooth loss. The main clinical issue in the treatment of periapical periodontitis is the repair of jawbone defects, and infection control is the first priority. However, the oral cavity is an open environment, and the distribution of microorganisms through the mouth in jawbone defects is inevitable. The subversion of host cell metabolism by oral microorganisms initiates disease. The presence of microorganisms stimulates a series of immune responses, which in turn stimulates bone healing. Given the above background, we intended to examine the paradoxes and connections between microorganisms and jaw defect repair in anticipation of new ideas for jaw defect repair. To this end, we reviewed the microbial factors, human signaling pathways, immune cells, and cytokines involved in the development of CAP, as well as concentrated growth factor (CGF) and stem cells in bone defect repair, with the aim of understanding the impact of microbial factors on host cell metabolism to inform the etiology and clinical management of CAP.

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Section: Ranklmentioning

confidence: 99%

Mechanisms of bone remodeling and therapeutic strategies in chronic apical periodontitis

Xu-tao

Wan

Liu

et al. 2022

Front. Cell. Infect. Microbiol.

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“…The effect of Notch3 ASOs was tested in cells of the osteoblast lineage since previous work demonstrated that Notch3 is preferentially expressed in these cells and is not expressed in cells of the myeloid lineage [ 16 , 51 , 52 ]. Mouse Notch3 ASOs added to the culture medium of osteoblast-enriched cells from C57BL/6 mice at 20 μM decreased Notch3 mRNA by ~60 to 80% 72 h after ASO addition without microscopic evidence of cellular toxicity or substantial changes in cell replication ( Fig 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…Notch3 ASOs decreased Notch3 mRNA in osteoblasts and bone marrow stromal cells from wild type and Notch3 em1Ecan mice and Notch3 6691TAAGTA mutant mRNA in Notch3 em1Ecan cells for periods of up to 21 days ( Fig 2 ). The inhibitory effect of Notch3 ASOs was also observed in osteocyte-enriched cells, a cellular environment that preferentially expresses Notch3 [ 51 , 52 ]. In this culture system, Notch3 ASOs inhibited Notch3 expression in wild type and Notch3 em1Ecan mice and also suppressed the expression of Notch3 6691-TAATGA mRNA in Notch3 em1Ecan mutant cells, although this effect did not reach statistical significance ( Fig 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…BV/TV (%) was (n = 16) 15.0 ± 2.3 in Notch3 em1Ecan mice treated with control ASO and (n = 14) 16.4 ± 3.3 in Notch3 em1Ecan mice treated with Notch3 ASO. Therefore, the effect of Notch3 ASO was limited to the cortical bone osteopenia, possibly because Notch3 is preferentially expressed by the osteocyte and cortical bone is enriched in these cells [ 51 , 52 ].…”

Section: Resultsmentioning

confidence: 99%

“…The effect of Notch3 ASOs was not explored at other skeletal sites since μCT parameters of bone microarchitecture are only established for cortical and cancellous bone [ 41 ]. It is possible that Notch3 ASOs were more effective at the osteocyte-rich cortical compartment because Notch3 is preferentially expressed by these cells [ 11 , 51 – 53 ]. Although the work demonstrates that Notch3 and Notch3 6691-TAATGA mutant mRNA were downregulated in osteocyte-rich preparations, we did not demonstrate that Notch3 ASOs are more effective in this cell population following their administration in vivo .…”

Section: Discussionmentioning

confidence: 99%

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Use of antisense oligonucleotides to target Notch3 in skeletal cells

et al. 2022

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Notch receptors are determinants of cell fate and function, and play an important role in the regulation of bone development and skeletal remodeling. Lateral Meningocele Syndrome (LMS) is a monogenic disorder associated with NOTCH3 pathogenic variants that result in the stabilization of NOTCH3 and a gain-of-function. LMS presents with neurological developmental abnormalities and bone loss. We created a mouse model (Notch3em1Ecan) harboring a 6691TAATGA mutation in the Notch3 locus, and heterozygous Notch3em1Ecan mice exhibit cancellous and cortical bone osteopenia. In the present work, we explored whether Notch3 antisense oligonucleotides (ASO) downregulate Notch3 and have the potential to ameliorate the osteopenia of Notch3em1Ecan mice. Notch3 ASOs decreased the expression of Notch3 wild type and Notch36691-TAATGA mutant mRNA expressed by Notch3em1Ecan mice in osteoblast cultures without evidence of cellular toxicity. The effect was specific since ASOs did not downregulate Notch1, Notch2 or Notch4. The expression of Notch3 wild type and Notch36691-TAATGA mutant transcripts also was decreased in bone marrow stromal cells and osteocytes following exposure to Notch3 ASOs. In vivo, the subcutaneous administration of Notch3 ASOs at 25 to 50 mg/Kg decreased Notch3 mRNA in the liver, heart and bone. Microcomputed tomography demonstrated that the administration of Notch3 ASOs ameliorates the cortical osteopenia of Notch3em1Ecan mice, and ASOs decreased femoral cortical porosity and increased cortical thickness and bone volume. However, the administration of Notch3 ASOs did not ameliorate the cancellous bone osteopenia of Notchem1Ecan mice. In conclusion, Notch3 ASOs downregulate Notch3 expression in skeletal cells and their systemic administration ameliorates cortical osteopenia in Notch3em1Ecan mice; as such ASOs may become useful strategies in the management of skeletal diseases affected by Notch gain-of-function.

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Antisense oligonucleotides targeting a NOTCH3 mutation in male mice ameliorate the cortical osteopenia of lateral meningocele syndrome

Canalis,

Mocarska,

Schilling

et al. 2023

Bone

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Activation of Notch3 in osteoblasts/osteocytes causes compartment-specific changes in bone remodeling

Cited by 5 publications

References 81 publications

Mechanisms of bone remodeling and therapeutic strategies in chronic apical periodontitis

Mechanisms of bone remodeling and therapeutic strategies in chronic apical periodontitis

Use of antisense oligonucleotides to target Notch3 in skeletal cells

Antisense oligonucleotides targeting a NOTCH3 mutation in male mice ameliorate the cortical osteopenia of lateral meningocele syndrome

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